Apoptosis is a normal physiological process by which multicellular organisms maintain cell number. Deregulation of apoptosis may be involved in tumorigenesis. It is known that tumor suppressor protein p53, oncoprotein bcl-2, bax, myc, myb, and Apo1/Fas are components of the apoptotic pathway. In the immune system, apoptotic signals can be triggered by steroid hormones and cytokines. However, little is known about the apoptotic signals and the molecular mechanisms in tissues of epithelial origin such as gastrointestinal tract and breast. Cell proliferation and differentiation are modulated not only by steroid hormones and cytokines but also by dietary compounds such as flavanoids and retinoids. Furthermore, dietary manipulation such as caloric restriction modulates cellular proliferation either directly or indirectly by altering the hormonal status of experimental animals. Thus, it is possible that dietary or nutritional factors may lead to modulation of apoptosis. We are interested in exploring dietary and nutritional effects on apoptosis. Our initial focus will be on modulation of the apoptosis related proteins. The apoptosis related proteins p53, bcl-2, bax, myc, myb, and Apo1 will be examined at the transcriptional, translational, and posttranslational level to elucidate possible effects. In addition, we will develop cell culture system(s) that will allow us to identify dietary factors which modulate apoptosis. We will also explore the process of apoptosis at the whole animal level. Genetically engineered p53-knockout mice will be used to study the relationship between p53 and other apoptosis related proteins. In addition, dietary manipulation of p53-knockout mice may reveal effects of dietary factors on apoptosis.